Performance Characteristics of Basophil Activation Tests for Diagnosing Penicillin Allergy: A Meta-Analysis.

BACKGROUND: Approximately 10% of the global population identify themselves as penicillin allergic, yet 90% are not truly allergic and could safely tolerate penicillin. There is no simple way to identify these people. Current in vitro diagnostics include specific immunoglobulin E (with a sensitivity of 19% and specificity of 97%) and a basophil activation test (BAT) with undefined sensitivity and specificity. OBJECTIVE: To define the sensitivity and specificity of BAT in the diagnosis of penicillin allergy METHODS: We searched PubMed and EMBASE from inception to April 2, 2023, for original studies evaluating the performance characteristics of BAT for penicillin allergy in adults. Study selection, data extraction, risk of bias, assessment with QUADAS-2 tool, certainty assessment with Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology were performed independently, in duplicate. Meta-analysis was performed using Reitsma methodology. RESULTS: Twenty-two studies fulfilled the inclusion criteria. Twelve used the same positive threshold giving a summary point sensitivity 51% (95% confidence interval [95% CI]46%-56%) and specificity 89% (95% CI 85%-93%). Significant risk of bias was identified owing to patient selection. GRADE certainty of evidence rated sensitivity very low due to imprecision and specificity as low. There was great heterogeneity in methods used. Use of 1,000 basophils per test did not improve performance above 500 basophils. CONCLUSIONS: BAT sensitivity is highly variable across studies and remains too low to be considered as a routine element of clinical practice. BAT specificity is not as good as specific immunoglobulin E in penicillin allergy diagnosis. Significant further work is required in this field before clinical application of BAT in routine practice.

Cerebral oximetry in adult cardiac surgery to reduce the incidence of neurological impairment and hospital length-of-stay: A prospective, randomized, controlled trial.

Background: Cerebral oximetry using near-infrared spectroscopy (NIRS) has been shown to reduce neurological dysfunction and hospital length-of-stay after adult cardiac surgery in some but not all studies. We audited maintaining cerebral saturations at or above baseline and showed improved neurological and length-of-stay outcomes. Our hypothesis for this study was that our NIRS protocol would improve neurological and length-of-stay outcomes. Methods: This prospective, single centre, double-blinded controlled study randomized 182 consecutive patients, scheduled for cardiac surgery using cardiopulmonary bypass. Participants were randomized by concealed envelope prior to anaesthesia. NIRS study group were managed perioperatively using our NIRS protocol of 8 interventions, increase cardiac output, normocapnia, increase mean arterial pressure, increase inspired oxygen, depth of anaesthesia, blood transfusion, correction of bypass cannula, change of surgical plan to restore levels equal to or above baseline. The control group had standard management without NIRS. Primary outcomes were neurological impairment (early and late) and hospital length-of-stay. Secondary outcomes were ventilation times, intensive care length-of-stay, major organ dysfunction and mortality. Results: 91 patients entered each group. There was a significant improvement in self-reported six-month general functionality in the NIRS group (p = 0.016). Early neurological dysfunction and hospital length-of-stay was the same in both groups. Of the secondary outcomes only Intensive Care length-of-stay was statistically significant, being shorter in the NIRS group (p = 0.026). Conclusion: Maintaining cerebral saturations above baseline reduces time spent in Intensive Care and may improve long term functional recovery but not stroke, major organ dysfunction and mortality.

Outcomes in Cardiac Surgery Based on Preoperative, Mean Intraoperative and Stratified Cerebral Oximetry Values.

INTRODUCTION: Cardiac surgery is associated with significant morbidity and longer length-of-stay (LOS) than most other surgeries. Regional cerebral oximetry (rSO2) using near-infrared spectroscopy (NIRS) on the patient's forehead monitors cerebral oxygenation during surgery and cardiopulmonary bypass (CPB). Its purpose is to detect and manage periods of cerebral hypoxia which may otherwise go undetected, thereby reducing morbidity. But outcomes have been inconsistent, and not all cardiac departments have adopted this non-invasive, simple-to-use technology. We aimed to study the efficacy of our use of rSO2 by recording seven outcomes for each patient according to their preoperative rSO2, the mean intraoperative rSO2, and four ischemic thresholds during surgery. METHOD: This is a retrospective audit of cardiac surgical patients in whom a protocol was used to maintain rSO2 above the preoperative value and studied seven major morbidity outcomes. Cerebral oximetry data were recorded for each patient and analyzed for six variables: preoperative baseline rSO2, mean intraoperative rSO2, and four ischemic thresholds defined as an area under the curve (AUC) in minutes% below the baseline rSO2,minus 10% below the baseline, minus 20% the below baselineand minus 50% below baseline. Outcomes examined were: delirium, stroke, postoperative rise in creatinine of 50 mmol, absolute creatinine of 200 mmol, need for new renal replacement therapy (RRT), hospital LOS and inpatient mortality. RESULTS: Complete data were available for 166 patients. Lower mean preoperative rSO2 was associated with stroke (p=0.031), mild and severe renal dysfunction (p=0.045 and p=0.036), death-in-hospital (p=0.027) and prolonged hospital LOS (p=0.005). Lower mean intraoperative rSO2 during surgery was associated with the outcomes of renal dysfunction, mild (p=0.027), moderate (p=0.003) or severe (p=0.002), death-in-hospital (p=0.003) and prolonged hospital LOS (p=0.015). Of the four ischemic thresholds defined, only new RRT occurring at minus 20% and minus 50% below baseline was significant. CONCLUSION: Lower preoperative rSO2 and mean intraoperative rSO2 were associated with poor outcomes, notably leading to a significant increase in hospital LOS. Mild degrees of cerebral ischemia below the baseline and minus 10% of the baseline during surgery were well tolerated.

Effect of Acute Stress Glycemic Control and Long-Term Glycemic Control on the Incidence of Post-Operative Infection in Diabetics Undergoing Cardiac Surgery.

Objective Post-operative infection after cardiac surgery causes prolonged hospital stay and increased mortality. In patients with diabetes, peri-operative and pre-operative glycemic control have been associated with increased risk of post-operative infection. Saudi Arabia is the 7th highest country in the world for the prevalence of diabetes. In our surgical population the incidence of diabetes is 77%. We were aware of a high incidence of post-operative infections in our institution. The aim of this work was to assess how peri-operative and pre-operative glycemic control was related to the six-week incidence of post-operative infection. Method We retrospectively collected data for 174 adult patients with diabetes undergoing cardiac surgery between January 2017 and June 2019. For group analysis of peri-operative glycemic control, a mean value of ≤10 mmol/l was categorized as optimal control and a mean value of >10 mmol/l as sub-optimal control. The admission glucose value, the maximum glucose value and glycosylated hemoglobin A1c (HbA1c) were separately recorded. Admission HbA1c was used for optimal long-term control group (HbA1c ≤ 7%) and sub-optimal long-term control group (HbA1c > 7%). Results Of the 174 patients 60 (34%) developed infection in the six-week post-operative period. No statistically significant difference in infections was seen in the optimal peri-operative control group (n = 24, 14%) compared to sub-optimal peri-operative control group (n = 36, 21%; p = 0.113). However, patients with infection had a significantly higher mean glucose (10.4 mmol/l versus 9.9 mmol/l, p = 0.0316) than no infection. Grouping according to their HbA1c: well controlled group (41, 24.0%) and poor control group (130, 76.0%) showed no difference in infections. However, patients with lower HbA1c had better glycemic control as measured by: initial glucose (r = 0.52, p=<0.001); mean peri-operative glucose (r = 0.45, p=<0.001); maximum recorded glucose (r = 0.41, p=<0.001). Conclusion The majority of our patients presented with sub-optimal long-term glycemic control which we linked to poor stress glycemic control perioperatively. Patients with post-operative infections had higher mean peri-operative blood glucose. With the high incidence of diabetes in Saudi Arabia we have demonstrated the importance of good pre-operative assessment which allows tighter peri-operative glycemic control to reduce post-operative morbidity.

The impact of regular bisoprolol on the response to salbutamol in asthma: A double-blind randomized placebo-controlled crossover trial.

BACKGROUND AND OBJECTIVE: Non-selective beta-blockers impair the bronchodilator response to beta2 -agonists. Cardio-selective beta1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta1 -blocker treatment in people with asthma. METHODS: A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 µg) was administered via spacer at 5-min intervals with repeated FEV1 measures. The FEV1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. RESULTS: A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. CONCLUSION: The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta1 -blocker, bisoprolol, compared to placebo. CLINICAL TRIAL REGISTRATION: ACTRN12618000306213 at https://www.anzctr.org.au.

A Case of Life-Threatening Airway Obstruction Caused by Acute Diphtheria Infection in the United Kingdom.

Diphtheria is a highly contagious and potentially life-threatening infection. Cases in the United Kingdom are rare due to widespread vaccination. However, in recent years, there has been a notable increase in cases in the United Kingdom. We present the case of a 76-year-old British Caucasian female who presented to the Emergency Department with shortness of breath and "chest tightness." She reported a five-day history of worsening sore throat, odynophagia, and aphonia. On inspection, she had noisy, laboured breathing with the use of her accessory muscles. Flexible laryngoscopy revealed purulent, thick yellow discharge in the nasal cavity, oropharynx, and supraglottis, with oedema of the subglottic mucosa. She became increasingly breathless and was peri-arrest when emergency orotracheal intubation was performed. She was transferred to the Intensive Care Unit for ventilatory support and intravenous antibiotics. Four days after presentation, her microbiology results confirmed toxigenic Corynebacterium ulcerans. Public Health England was informed immediately. The patient was isolated and contact tracing was commenced. Thirty staff members were required to self-isolate and take prophylactic antibiotics due to close patient contact. It was particularly noteworthy that our patient was a UK national with no recent history of foreign travel. This case demonstrates the importance of remaining vigilant to atypical causes of airway obstruction secondary to infection. Early suspicion and prompt patient isolation may prevent community and occupational transmission and minimise the impact of contact tracing on hospital staffing. Migration from endemic countries and declining childhood vaccination rates may lead to a further rise in UK cases of diphtheria in the future.

AlphaE Integrin Expression Is Increased in the Ileum Relative to the Colon and Unaffected by Inflammation.

BACKGROUND: Recent findings suggest that αE expression is enriched on effector T cells and that intestinal αE+ T cells have increased expression of inflammatory cytokines. αE integrin expression is a potential predictive biomarker for response to etrolizumab, a monoclonal antibody against ß7 integrin that targets both α4ß7 and αEß7. We evaluated the prevalence and localization of αE+ cells as well as total αE gene expression in healthy and inflammatory bowel disease patients. METHODS: αE+ cells were identified in ileal and colonic biopsies by immunohistochemistry and counted using an automated algorithm. Gene expression was assessed by quantitative reverse-transcriptase polymerase chain reaction. RESULTS: In both healthy and inflammatory bowel disease patients, significantly more αE+ cells were present in the epithelium and lamina propria of ileal compared with colonic biopsies. αE gene expression levels were also significantly higher in ileal compared with colonic biopsies. Paired biopsies from the same patient showed moderate correlation of αE expression between the ileum and colon. Inflammation did not affect αE expression, and neither endoscopy nor histology scores correlated with αE gene expression. αE expression was not different between patients based on concomitant medication use except 5-aminosalicylic acid. CONCLUSION: αE+ cells, which have been shown to have inflammatory potential, are increased in the ileum in comparison with the colon in both Crohn's disease and ulcerative colitis, as well as in healthy subjects. In inflammatory bowel disease patients, αE levels are stable, regardless of inflammatory status or most concomitant medications, which could support its use as a biomarker for etrolizumab.

Breast cancer metastasis: demonstration that FOXP3 regulates CXCR4 expression and the response to CXCL12.

The X-linked transcription factor FOXP3 is expressed by epithelial cells of organs including the breast, where it is considered a tumour suppressor. The chemokine receptor CXCR4 also regulates the development of breast cancer by stimulating cell migration towards CXCL12-expressing sites of metastatic spread. During activation, human T cells show reciprocal regulation of FOXP3 and CXCR4. This study was designed to examine the role FOXP3 plays in metastatic breast cancer, with a particular focus on its potential to regulate CXCR4. Human breast cancer samples showed significantly decreased FOXP3 protein expression but an increased number of CXCR4 transcripts. In comparison with normal primary breast epithelial cells, FOXP3 was down-regulated at both transcript and protein levels in the breast cancer cell lines MCF-7 and MDA-MB-231. In the invasive MDA-MB-231 cells, the remaining FOXP3 was located predominately within the cytoplasm. Following stable FOXP3 overexpression in MDA-MB-231 cells, significant decreases were observed in the expression of ErbB2/HER2, SKP2, c-MYC, and CXCR4. In contrast, an increase in p21 expression led to inhibition of cell proliferation, with a greater proportion in the G1 phase of the cell cycle suggesting the induction of senescence. Specific knockdown of FOXP3 in normal human breast epithelial cells with siRNA significantly increased ErbB2/HER2, SKP2, c-MYC, and CXCR4, and decreased p21 expression. These cells also showed a significantly increased chemotactic response towards CXCL12, consistent with a role for FOXP3 in the regulation of cell migration. Results from this study are consistent with FOXP3 functioning as an important tumour suppressor in breast cancer. Indeed, the potential functions of FOXP3 in breast epithelium can now be extended to include regulation of CXCR4 expression and response to the pro-metastatic chemokine CXCL12.